title: Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment.
abstract: Myelodysplastic syndromes (MDS) are common causes of ineffective hematopoiesis and cytopenias in the elderly. Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in MDS. We have previously shown that p38 MAPK is overactivated in MDS hematopoietic progenitors, which led to current clinical studies of the selective p38alpha inhibitor, SCIO-469, in this disease. We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow (BM) cells in a p38 MAPK-dependent manner. Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with CD34+ stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment. Treatment with SCIO-469 inhibits TNF secretion in primary MDS bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo. Furthermore, p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells. These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival. These findings support clinical investigation of p38alpha as a potential therapeutic target in MDS and other related diseases characterised by inflammatory bone marrow failure.
authors.affiliation: Scios Inc, Fremont, CA, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Navas
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Myka
authors.initials: M
authors.lastname: Estes
authors.forename: Edwin
authors.initials: E
authors.lastname: Haghnazari
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: Yongkai
authors.initials: Y
authors.lastname: Mo
authors.forename: Perry
authors.initials: P
authors.lastname: Pahanish
authors.forename: Mani
authors.initials: M
authors.lastname: Mohindru
authors.forename: Tim
authors.initials: T
authors.lastname: Cao
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Alan
authors.initials: A
authors.lastname: List
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.forename: T
authors.initials: T
authors.lastname: Bhagat
authors.forename: S
authors.initials: S
authors.lastname: Gajavelli
authors.forename: S
authors.initials: S
authors.lastname: Kambhampati
mesh_terms: D000368:Aged; D001853:Bone Marrow / Q000473:pathology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D053583:Interleukin-1beta / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000473:pathology*; D019899:Paracrine Communication / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; C499748:SCIO-469; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases